Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth.

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells.

BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. MATERIAL AND METHODS: We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. RESULTS: MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. CONCLUSIONS: Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.

Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.

Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the specific alteration of the cytochrome c oxidase (COX), representing a common defect found in mitochondrial diseases, facilitates mitochondrial apoptosis in response to oxidative stress. Our data identified an increased ceramide synthase 6 (CerS6) activity as an important pro-apoptotic response to COX dysfunction induced either by chemical or genetic approaches. The elevated CerS6 activity resulted in accumulation of the pro-apoptotic C16 : 0 ceramide, which facilitates the mitochondrial apoptosis in response to oxidative stress. Accordingly, inhibition of CerS6 or its specific knockdown diminished the increased susceptibility of COX-deficient cells to oxidative stress. Our results provide new insights into how mitochondrial RC dysfunction mechanistically interferes with the apoptotic machinery. On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction.

Elevated XIAP expression alone does not confer chemoresistance.

BACKGROUND: In various tumour types, elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been observed and XIAP targeting in diverse tumour entities enhanced the susceptibility to chemotherapeutic agents. Therefore, XIAP has been described and reviewed repeatedly as a chemoresistance factor in different tumour entities. However, rather than being an adverse prognostic marker, recent data suggest that elevated XIAP expression may be associated with a favourable clinical outcome. These somewhat conflicting findings, and the fact that in early studies XIAP suppressed apoptosis only when expressed transiently at levels far in excess of its physiological concentration, argue that the function of XIAP as an anti-apoptotic factor in tumour cells is both more complex and diverse than previously appreciated. METHODS: To better understand the impact of long-term elevated XIAP expression on resistance to chemotherapy, we generated cell lines stably overexpressing XIAP. The role of mitochondria was examined by stable expression of Bcl2 or stable knockdown of second mitochondria-derived activator of caspase (SMAC) in combination with up- or downregulation of XIAP expression. RESULTS: Our data show that long-term expression of XIAP at concentrations comparable to that in tumour cells (two- to five-fold increase) resulted in little or no resistance towards chemotherapeutic drugs. The XIAP overexpression only in conjunction with stable knockdown of a single XIAP-antagonising factor such as SMAC resulted in severe resistance to cytostatic agents demonstrating XIAP as a potent chemoresistance factor only in cells lacking functional XIAP regulatory circuits. CONCLUSION: Our results demonstrated that elevated XIAP expression alone cannot serve as a predictive marker of chemoresistance. Our data suggest that in order to predict the impact of XIAP on chemosusceptibility for a given tumour entity, the expression levels and functional states of all XIAP modulators need to be taken into account.

Prevention and management of sigmoid and pelvic ischemia associated with aortic surgery.

Ischemia of the colon, rectum, and pelvis continues to be a significant source of morbidity and mortality after aortic reconstruction. Complications associated with colonic and pelvic ischemia are severe and include impotency, buttock claudication, colonic and rectal infarction, buttock and perineal necrosis, and spinal cord or lumbar plexus injury. To prevent these complications the vascular surgeon must make every attempt to guarantee the adequacy of colonic and pelvic blood supply after aortic reconstructive procedures. During open surgical repair of aneurysms or aortoiliac arterial occlusive disease, patent inferior mesenteric arteries must either be routinely reimplanted or selectively ligated on the basis of object intraoperative assessment of colonic perfusion. In addition, when possible, antegrade perfusion should be maintained in patent internal iliac arteries, and femoral reconstructions should include reconstruction of the deep femoral artery to assure adequate perfusion of potential pelvic collaterals. The rate of colonic and pelvic ischemia after endovascular aneurysm repair appears lower than after open repair, but all of the complications of colonic and pelvic ischemic seen after open repairs have been reported after endoluminal aneurysm repair. Thus, during stent-graft repair of abdominal aortic aneurysms, all attempts also should be made to preserve pelvic perfusion by maintaining antegrade flow to a least one patent internal iliac artery. The principle to remember in the management of complications of pelvic ischemia associated with aortic reconstruction is prevention because when complications of pelvic ischemia occur, the damage often is irreversible.

Contribution of the Southern Association for Vascular Surgery to the scientific literature.

The Southern Association for Vascular Surgery (SAVS) has played a significant role in the development and evolution of vascular surgery. This study was designed to document the contribution to the scientific literature and to highlight the important publications from the annual meetings of the SAVS on its 25th anniversary. A total of 413 (73%) of the 569 "free papers" presented at the SAVS Annual Meeting were published in journals that are identified in MEDLINE, and most (71%) were published in the Journal of Vascular Surgery. Carotid/cerebrovascular disease, leg ischemia, and basic considerations were the most common subject matters overall, although there has been a recent decrease in the percentage of articles about basic considerations and aortic aneurysms while there has been an increase in those about endovascular therapy, vascular laboratory/imaging, and visceral/renal artery disease. The 413 papers were cited a mean of 18 +/- 20 (+/- SD) times (range 0-143) with 32 papers cited more than 39 times and 17 papers cited more than 59 times. A panel of three reviewers identified 42 significant articles, among which 8 were considered seminal by 2 of the 3 reviewers. The papers presented at the annual meeting of the SAVS have made a significant contribution to the scientific literature in terms of both quantity and quality. These efforts have laid the foundation for the next quarter century and have raised the level of expectation.

A model for evaluation of arterial thrombosis following interventional procedures.

A model to assess thrombus formation following vascular injury was evaluated using various interventional systems. The model consisted of a 'stretchable' shunt box that served as an arteriovenous shunt between the carotid artery and jugular vein in dogs. Arterial homografts obtained from both carotid and femoral arteries were mounted between two plastic connectors attached to either side of the shunt box. The opposing walls of the shunt box were then stretched apart to achieve the original length of the arteries. The arterial side of the box was connected to the ipsilateral carotid artery and the venous side was connected to the contralateral jugular vein. Haemostasis valves were placed at the exit ports on the venous side of the shunt box. These were used as an access to the various interventional catheters into the lumens of the homografts. Interventions were performed prior to initiating blood flow. After the interventions, 111indium-labelled platelets were injected on the arterial side of the shunt box and arterial blood flow initiated across the shunt. After one hour of circulation through the shunt box, the blood flow was interrupted, and the homografts were perfusion-fixed with glutaraldehyde and segments removed for radioactive counts and processed for histology. This shunt box was then used to compare platelet adhesion and thrombus formation after balloon angioplasty (BA) to direct laser (LA) and laser-thermal angioplasty (LTA). A total of 28 arteries were used from seven dogs. In each experiment, one homograft was used as control, and three other homografts were treated with either BA, LA or LTA. Following the interventions, 111indium-labelled platelets were injected and circulated for one hour using the dog's native circulation. Labelled platelet counts for BA (19102+/-4869/cm2; mean +/- SE) were significantly greater than LA (7038+/-980/cm2), thermal LTA (5189+/-1961/cm2), and control (1575+/-541/cm2), respectively (p<0.05, ANOVA). Histology examination showed few platelets at LA, LTA and control sites whereas extensive platelet adhesion was noted at BA treated sites. The model provided a means to conduct simultaneous comparison of several interventions under similar conditions. In this case thermal treatment of the arterial homografts had the least amount of platelet adhesion.

The outcome in the United States after thoracoabdominal aortic aneurysm repair, renal artery bypass, and mesenteric revascularization.

OBJECTIVES: The purpose of this study was to determine outcome and identify predictors of death after thoracoabdominal aortic aneurysm (TAA) repair, renal artery bypass (RAB), and revascularization for chronic mesenteric ischemia (CMI). PATIENTS AND METHODS: In this retrospective analysis, data were obtained from the Nationwide Inpatient Sample, a 20% all-payer stratified sample of hospitals in the United States during 1993 to 1997. Patients were identified by the presence of a diagnostic or procedure code from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The main outcomes we examined were death, ICD-9-CM -based complications, length of stay, hospital charges, and disposition. A multivariate model was constructed to predict death. RESULTS: A total of 2934 patients were identified (TAA, 540; RAB, 2058; CMI, 336) in the database. The mean age was comparable (TAA, 69 +/- 9 years; RAB, 66 +/- 12 years; CMI, 66 +/- 11 years), but the breakdown between the sexes varied by procedure (male: TAA, 53%; RAB, 55%; CMI, 24%). The mortality rate (TAA, 20.3%; RAB, 7.1%; CMI, 14.7%), complication rate (TAA, 62.2%; RAB, 37.4%; CMI, 44.6%), and the percentage of patients discharged to another institution (TAA, 21.2%; RAB, 9.3%; CMI, 12.0%) were clinically significant for all procedures. The mortality rate for RAB was greater when performed concomitant with an aortic reconstruction (4.4% vs 8.3%). All three procedures were resource intensive as reflected by the median length of stay (TAA, 14 days; RAB, 9 days; CMI, 14 days) and median hospital charges (TAA, $64,493; RAB, $36,830; CMI, $47,390). The multivariate model identified several variables for each procedure that had an impact on the predicted mortality rate (TAA, 14%-76%; RAB, < 1%-46%; CMI, < 2%-87%). CONCLUSIONS: The operative mortality rates across the United States for patients undergoing TAA repair and RAB are greater than commonly reported in the literature and mandate reexamining the treatment strategies for these complex vascular problems.

External-beam radiation therapy for improved dialysis access patency: feasibility and early safety.

Rectenwald, J. E., Pretus, H. A., Seeger, J. M., Huber, T. S., Mendenhall, N. P., Zlotecki, R. A., Palta, J. R., Li, Z. F., Hook, S. Y., Sarac, T. P., Welborn, M. B., Klingman, N. V., Abouhamze, Z. S. and Ozaki, C. K. External-Beam Radiation Therapy for Improved Dialysis Access Patency: Feasibility and Early Safety. Radiat. Res. 156, 53-60 (2001).Prosthetic dialysis access grafts fail secondary to neointimal hyperplasia at the venous anastomosis. We hypothesized that postoperative single-fraction external-beam radiation therapy to the venous anastomosis of hemodialysis grafts can be used safely in an effort to improve access patency. Dogs (n = 8) underwent placement of expanded polytetrafluoroethylene grafts from the right carotid artery to the left jugular vein. Five dogs received single-fraction external-beam photon irradiation (8 Gy) to the venous anastomosis after surgery. Controls were not irradiated. Shunt angiograms were completed 3 and 6 months postoperatively. Anastomoses, mid-graft, and the surrounding tissues were analyzed. Immunohistochemistry for smooth muscle cell alpha-actin, proliferating cellular nuclear antigen (PCNA), and apoptosis was performed. Incisions healed well, though all animals developed wound seromas. One control suffered graft thrombosis 4 months postoperatively. Angiography/histology confirmed severe neointimal hyperplasia at the venous anastomosis. The remaining seven dogs developed similar amounts of neointimal hyperplasia. PCNA studies showed no accelerated fibroproliferative response at irradiated anastomoses compared to controls. Skin incisions and soft tissues over irradiated anastomoses revealed no radiation-induced changes or increase in apoptosis. Thus we conclude that postoperative single-fraction external-beam irradiation of the venous anastomosis of a prosthetic arteriovenous graft that mimics the situation in humans is feasible and safe with regard to early wound healing.

Experience in the United States with intact abdominal aortic aneurysm repair.

OBJECTIVES: The purpose of this study was to determine the current outcome in the United States and to identify predictors of mortality and "bad outcome" after open, intact abdominal aortic aneurysm (AAA) repair. METHODS: In a retrospective analysis, data were obtained from the Nationwide Inpatient Sample during 1994-1996. The Nationwide Inpatient Sample is a 20% all-payer stratified sample of nonfederal United States hospitals. Patients older than 49 years were identified by the presence of primary diagnostic (441.4-intact AAA) and procedure (38.44-resection of abdominal aorta with replacement) codes of the International Classification of Diseases, Ninth Revision (ICD-9 ). In-hospital mortality rate, discharge disposition, bad outcome (death or discharge to an institution), complications (ICD-9 postoperative codes), length of stay, and charges were determined. The mortality rate and bad outcome were analyzed by the use of patient demographics (age, sex, race), patient comorbidities (ICD-9 diagnostic codes), calendar year, and hospital characteristics (size, location, teaching status) with univariate and multivariate analyses. RESULTS: We identified 16,450 intact AAAs repairs during the study years. The mean patient age was 72 +/- 7 (+/- SD) years, and most patients were male (79.7%) and white (94.6%). Most repairs were performed at large (67.3%), urban (92.5%), and nonteaching (66.7%) institutions. The in-hospital mortality rate was 4.2%, the overall complication rate was 32.4%, and 91.2% of patients were discharged home, whereas the bad outcome rate was 12.6%. The median length of stay was 8 days (mean, 10.0 +/- 8.1), and median hospital charges were $28,052 (mean, $35,681 +/- $33,006) in 1996 dollars. Multivariate analysis showed that the mortality rate (P <.05) increased with age (70-79 years, 1.8 odds ratio [OR] [95% CI, 1.4-2.3], > 79 years, 3.8 OR [95% CI, 2.9-4.9]), sex (female, 1.6 OR [95% CI, 1.3-1.9]), cerebral vascular occlusive disease (1.8 OR [95% CI, 1.3-2.5]), preoperative renal insufficiency (9.5 OR [95% CI, 7.7-11.7]), and more than three comorbidities (11.2 OR [95% CI, 3.6-35.4]). Multivariate analysis also showed that bad outcome was associated with the same variables in addition to hospital size (small/medium), year of procedure (1996), chronic obstructive pulmonary disease, and two to three comorbidities. CONCLUSIONS: Outcome after open repair of intact AAA across the United States is quite good. Older, sicker patients may benefit from nonoperative treatment or the potentially lower risk endovascular approaches.

Direct evidence for cytokine involvement in neointimal hyperplasia.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addition, TNF-alpha and IL-1 influence vascular smooth muscle cell migration and proliferation in vitro. In view of the inflammatory nature of neointimal hyperplasia (NIH), we tested the hypothesis that endogenous TNF-alpha and IL-1 modulate low shear stress-induced NIH. METHODS AND RESULTS: Mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated CCA has previously been shown to result in remodeling and NIH. Reverse transcriptase-polymerase chain reaction for TNF-alpha and IL-1alpha mRNA demonstrated both TNF-alpha and IL-1alpha mRNA in ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-alpha (TNF-/-) developed 14-fold less neointimal area than WT controls (P:<0.05). p80 IL-1 type I receptor knockout (IL-1RI-/-) mice tended to develop less (7-fold, P:>0.05) neointimal area than WT controls. Furthermore, no IL-1alpha mRNA expression was detected in CCAs from TNF-/- mice; however, TNF-alpha mRNA expression was found in the IL-1RI-/- mice. Mice that overexpress membrane-bound TNF-alpha but produce no soluble TNF-alpha display an accentuated fibroproliferative response to low shear stress (P:<0.05). CONCLUSIONS: These results directly demonstrate that TNF-alpha and IL-1 modulate NIH induced by low shear stress. NIH can proceed by way of soluble TNF-alpha-independent mechanisms. Specific anti-TNF-alpha and anti-IL-1 therapies may lessen NIH.

The relationship between visceral ischemia, proinflammatory cytokines, and organ injury in patients undergoing thoracoabdominal aortic aneurysm repair.

OBJECTIVES: Plasma proinflammatory, anti-inflammatory cytokine, and soluble tumor necrosis factor (TNF) receptor concentrations were examined in hospitalized patients after abdominal and thoracoabdominal aortic aneurysm (TAAA) repair, with and without left atrial femoral bypass. Changes in plasma cytokine concentrations were related to the duration of visceral ischemia and the frequency rate of postoperative, single, or multiple system organ dysfunction (MSOD). DESIGN: Prospective, observational study. SETTING: Two academic referral centers in the United States and The Netherlands. PATIENTS: We included 16 patients undergoing TAAA repair without left atrial femoral bypass, 12 patients undergoing TAAA repair with left atrial femoral bypass, and nine patients undergoing infrarenal aortic aneurysm repair. MEASUREMENTS AND MAIN RESULTS: Timed, arterial blood sampling for proinflammatory and anti-inflammatory cytokine and soluble TNF receptor concentrations (p55 and p75), and prospective assessment of postoperative single and MSOD. Plasma appearance of TNF-alpha, interleukin (IL)-6, IL-8, and IL-10 peaked 1 to 4 hrs after TAAA repair, and concentrations were significantly elevated compared with infrarenal abdominal aortic aneurysm repair (p < .05). Left atrial femoral bypass significantly reduced the duration of visceral ischemia (p < .05) and the systemic TNF-alpha, p75, and IL-10 responses (p < .05). Plasma TNF-alpha concentrations >150 pg/mL were more common in patients with extended visceral ischemia times (>40 mins). Additionally, patients with early peak TNF-alpha concentrations >150 pg/mL and IL-6 levels >1,000 pg/mL developed MSOD more frequently than patients without these elevated plasma cytokine levels (both p < .05). CONCLUSIONS: Thoracoabdominal aortic aneurysm repair results in the increased plasma appearance of TNF-alpha, IL-6, IL-8, IL-10, and shed TNF receptors. The frequency and magnitude of postoperative organ dysfunction after TAAA repair is associated with an increased concentration of the cytokines, TNF-alpha, and IL-6 and the increased plasma levels of these cytokines appear to require extended visceral ischemia times.

Long-term outcome after treatment of aortic graft infection with staged extra-anatomic bypass grafting and aortic graft removal.

OBJECTIVE: The purpose of this study was to determine long-term outcome in patients with infected prosthetic aortic grafts who were treated with extra-anatomic bypass grafting and aortic graft removal. METHODS: Between January 1989 and July 1999, 36 patients were treated for aortic graft infection with extra-anatomic bypass grafting and aortic graft removal. Extra-anatomic bypass graft types were axillofemoral femoral (5), axillofemoral (26; bilateral in 20), axillopopliteal (3; bilateral in 1) and axillofemoral/axillopopliteal (2). The mean follow-up was 32.3 +/- 4. 8 months. RESULTS: Four patients (11%) died in the postoperative period, and two patients died during follow-up as a direct consequence of extra-anatomic bypass grafting and aortic graft removal (one died 7 months after extra-anatomic bypass graft failure, one died 36 months after aortic stump disruption). One additional patient died 72 months after failure of a subsequent aortic reconstruction, so that the overall treatment-related mortality was 19%, whereas overall survival by means of life table analysis was 56% at 5 years. No amputations were required in the postoperative period, but four patients (11%) required amputation during follow-up. Twelve patients (35%) had extra-anatomic bypass graft failure during follow-up, and six patients underwent secondary aortic reconstruction (thoracobifemoral [2], iliofemoral [2], femorofemoral [2]). However, with the exclusion of patients undergoing axillopopliteal grafts (primary patency 0% at 7 months), only seven patients (25%) had extra-anatomic bypass graft failure, and only two patients required amputation (one after extra-anatomic bypass graft removal for infection, one after failure of a secondary aortic reconstruction). Furthermore, primary and secondary patency rates by means of life table analysis were 75% and 100% at 41 months for axillofemoral femoral grafts and 64% and 100% at 60 months for axillofemoral grafts. Only one patient required extra-anatomic bypass graft removal for recurrent infection, and only one late aortic stump disruption occurred. CONCLUSIONS: Staged extra-anatomic bypass grafting (with axillofemoral bypass graft) and aortic graft removal for treatment of aortic graft infection are associated with acceptable early and long-term outcomes and should remain a primary approach in selected patients with this grave problem.

Laparotomy prevents lethal endotoxemia in a murine sequential insult model by an IL-10-dependent mechanism.

Multiple organ dysfunction and death are common sequelae after mesenteric ischemia-reperfusion injury as seen with mesenteric revascularization and thoracoabdominal aortic aneurysm repair. A second insult such as bacterial pneumonia occurring subsequent to the ischemia-reperfusion injury may contribute to these untoward effects. We hypothesized the sequential visceral/lower torso ischemia-reperfusion and endotoxemia in a murine model would increase the magnitude of the proinflammatory cytokine response and decrease survival. C57BL/6 mice underwent 20 min of supraceliac occlusion (IR), sham laparotomy (LAP), or no initial insult (CTRL) followed by intraperitoneal injection of a lethal dose of endotoxin (LPS [lipopolysaccharide 50 mg/kg] or saline vehicle at 24 h. Serum cytokine levels were measured by enzyme-linked immunosorbent assay (IL-10, IL-6) or WEHI bioassay [tumor necrosis factor (TNF)], and survival was determined at 5 days. The role of IL-10 on the TNF response and survival was examined in a subset of mice given mouse anti IL-10 IgM (25 mg/kg intraperitoneally) 2 h prior to the initial insult. Survival after LPS was significantly different (P < 0.05) among the treatment groups (IR, 64%; LAP, 55%; CTRL, 11%) and appeared to trend directly with the magnitude of the initial operation. The serum IL-10 levels in the IR and LAP groups were significantly increased 4 h after the initial insult and remained elevated at 24 h. Peak serum TNF levels after LPS were significantly lower in the IR and LAP groups. Administration of anti IL-10 IgM resulted in uniform mortality and a significant increase in the peak TNF levels after LPS administration for all initial treatment groups. Endogenous production of IL-10 following laparotomy down-regulates the TNF response and improves survival after endotoxemia.

Interleukin-10 appearance following thoraco-abdominal and abdominal aortic aneurysm repair is associated with the duration of visceral ischaemia.

OBJECTIVES: to evaluate the plasma IL-10 levels during elective operative repair of thoraco-abdominal and abdominal aortic aneurysm repair. To study whether IL-10 plasma levels are associated with the duration of cross-clamping (ischaemia) and clinical outcome. MATERIALS: fifteen consecutive patients undergoing surgery for TAAA and 10 consecutive patients undergoing surgical repair of AAA were included. METHODS: plasma concentrations of IL-10 were measured by ELISA technique. Clinical outcome of the TAAA patients was prospectively analysed. RESULTS: during aortic clamping IL-10 was produced in both populations. The plasma IL-10 peak (934+/-172 pg/ml) of the TAAA group was seen at 4 h after declamping and remained detectable after 48 h. The plasma IL-10 peak (212+/-32 pg/ml) of the AAA group was seen 30 min after declamping and fell to undetectable levels by 24 h. These data show that the peak IL-10 plasma levels in TAAA repair are significantly (p<0.05) higher compared to the peak IL-10 plasma levels as seen during AAA repair. A positive correlation was seen between cross-clamping and peak plasma IL-10 and organ dysfunction. CONCLUSIONS: IL-10 plasma concentrations appear higher, later and are longer detectable in patients undergoing TAAA. Correlations were seen with duration of cross-clamping and MSOD.

Anticytokine therapies for acute inflammation and the systemic inflammatory response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm.

The results of recent anticytokine trials for sepsis syndrome have been disappointing. Several Phase II and Phase III clinical trials have shown a modest benefit in various subsets of patients; however, there has been no reported benefit in the primary endpoint of 28-day all-cause mortality. The failure of these trials is clearly multifactorial, and causes include the overall complexity of the inflammatory response, heterogeneity of the patient populations, absence of a hypercytokine response at the time of drug treatment, and the relatively short half-life of the administered drugs. The failure of anticytokine therapies may represent inadequate application of the treatment modality rather than any inherent weakness of the treatment itself. We have recently initiated a Phase I clinical trial examining the role of the anti-inflammatory cytokine IL-10 during surgical repair of a thoracoabdominal aortic aneurysm. This study may overcome some of the-design limitations of previous anticytokine trials in sepsis, and serve as a paradigm for future anticytokine therapy trials. Although the incidence of thoracoabdominal aortic aneurysms is relatively low, the patient population is homogeneous and the surgical injury associated with its repair reproducible. Additionally, postoperative mortality and morbidity rates are significant. Most importantly, the operative repair is associated with an obligatory visceral ischemia and reperfusion injury that appears to be associated with a proinflammatory cytokine response and postoperative organ dysfunction. IL-10 is a pleuripotent anti-inflammatory cytokine that both inhibits TNFalpha and IL-1 synthesis, and antagonizes their actions through upregulation of cytokine antagonists. Furthermore, IL-10 administration has been associated with only minimal adverse side effects during Phase I and Phase II trials.

Financial impact of tertiary care in an academic medical center.

OBJECTIVE: To analyze the financial impact of three complex vascular surgical procedures to both an academic hospital and a department of surgery and to examine the potential impact of decreased reimbursements. SUMMARY BACKGROUND DATA: The cost of providing tertiary care has been implicated as one potential cause of the financial difficulties affecting academic medical centers. METHODS: Patients undergoing revascularization for chronic mesenteric ischemia, elective thoracoabdominal aortic aneurysm repair, and treatment of infected aortic grafts at the University of Florida were compared with those undergoing elective infrarenal aortic reconstruction and carotid endarterectomy. Hospital costs and profit summaries were obtained from the Clinical Resource Management Office. Departmental costs and profit summary were estimated based on the procedural relative value units (RVUs), the average clinical cost per RVU ($33.12), surgeon charges, and the collection rate for the vascular surgery division (30.2%) obtained from the Faculty Group Practice. Surgeon work effort was analyzed using the procedural work RVUs and the estimated total care time. The analyses were performed for all payors and the subset of Medicare patients, and the potential impact of a 15% reduction in hospital and physician reimbursement was analyzed. RESULTS: Net hospital income was positive for all but one of the tertiary care procedures, but net losses were sustained by the hospital for the mesenteric ischemia and infected aortic graft groups among the Medicare patients. In contrast, the estimated reimbursement to the department of surgery for all payors was insufficient to offset the clinical cost of providing the RVUs for all procedures, and the estimated losses were greater for the Medicare patients alone. The surgeon work effort was dramatically higher for the tertiary care procedures, whereas the reimbursement per work effort was lower. A 15% reduction in reimbursement would result in an estimated net loss to the hospital for each of the tertiary care procedures and would exacerbate the estimated losses to the department. CONCLUSIONS: Caring for complex surgical problems is currently profitable to an academic hospital but is associated with marginal losses for a department of surgery. Economic forces resulting from further decreases in hospital and physician reimbursement may limit access to academic medical centers and surgeons for patients with complex surgical problems and may compromise the overall academic mission.

Use of superficial femoral vein for hemodialysis arteriovenous access.

Maintaining hemodialysis access in the expanding number of patients with end-stage renal disease is a difficult and challenging problem. Published guidelines outline the initial recommendations for hemodialysis access; however, there is little consensus about the most appropriate options for the subset of patients with repeated access failures and/or unsuitable veins. Two case reports are presented describing the use of composite saphenous-superficial femoral vein autogenous accesses placed in the upper and lower extremities. The function of the autogenous accesses appeared to be similar to a mature arteriovenous fistula in the short-term, although further longitudinal studies are required. The superficial femoral vein may be a useful hemodialysis access conduit for patients with limited access options.

Management of patients with prosthetic vascular graft infection.

Management of patients with infected prosthetic vascular grafts is one of the most difficult challenges faced by the vascular surgeon. Patients often present with nonspecific symptoms, but delay in treatment can lead to life-threatening sepsis and/or hemorrhage. Fortunately, prosthetic vascular graft infection is uncommon, with the incidence varying between 1 and 6 per cent, depending on the location of the graft. Initially, the potentially infected vascular graft should be imaged using either CT or magnetic resonance imaging, with radionuclide studies being reserved for those instances in which imaging studies do not confirm or exclude the diagnosis of infection. Current treatments for prosthetic vascular graft infection include attempted graft preservation, graft removal with in situ graft replacement (using autogenous or new prosthetic grafts), and graft removal with extra-anatomic bypass. Morbidity and mortality associated with treatment, likelihood of long-term limb salvage, and likelihood of persistent or recurrent infection vary among these types of treatment. Therefore, in an individual patient with a prosthetic vascular graft infection, many things must be considered to appropriately determine the treatment most likely to achieve eradication of the infection and long-term limb salvage with the lowest risk. Regardless, with appropriate application of the techniques currently available for treatment of prosthetic vascular graft infection, long-term elimination of infection and limb preservation can be achieved in the great majority of patients with this grave problem.